Accepted Manuscript Association Between Pancreatic IPMNs and Extra-pancreatic Malignancies Giovanni Marchegiani , Giuseppe Malleo , Jan G. D’Haese , Patrick Wenzel , Muharrem Keskin , Luigi Pugliese , Alex Borin , Valentina Benning , Linda Nilsson , Nevin Oruc , Ralf Segersvard , Helmut Friess , Roland Schmid , Matthias Löhr , Patrick Maisonneuve , Claudio Bassi , Güralp O. Ceyhan , Roberto Salvia , Marco Del Chiaro

PII: DOI: Reference:

S1542-3565(14)01723-6 10.1016/j.cgh.2014.11.029 YJCGH 54086

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 13 November 2014 Please cite this article as: Marchegiani G, Malleo G, D’Haese JG, Wenzel P, Keskin M, Pugliese L, Borin A, Benning V, Nilsson L, Oruc N, Segersvard R, Friess H, Schmid R, Löhr M, Maisonneuve P, Bassi C, Ceyhan GO, Salvia R, Del Chiaro M, Association Between Pancreatic IPMNs and Extra-pancreatic Malignancies, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/j.cgh.2014.11.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

ACCEPTED MANUSCRIPT Association Between Pancreatic IPMNs and Extra-pancreatic Malignancies

Short title: IPMN and extrapancreatic malignancies

Giovanni Marchegiani 1, Giuseppe Malleo 1, Jan G. D’Haese 2, Patrick Wenzel 3,

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Muharrem Keskin 4, Luigi Pugliese 5, Alex Borin 1, Valentina Benning 2, Linda Nilsson 6, Nevin Oruc 4, Ralf Segersvard 6, Helmut Friess 2, Roland Schmid 3, Matthias Löhr 7, Patrick

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Maisonneuve 8, Claudio Bassi 1, Güralp O. Ceyhan 2, Roberto Salvia 1*, and Marco Del Chiaro 6*

From the 1 Unit of Surgery B, The Pancreas Institute, University of Verona Hospital Trust, Verona,

Germany;

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Italy; 2 Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Department of Gastroenterology, Klinikum rechts der Isar, Technische Universität

München, Munich, Germany; 4 Division of Gastroenterology, Department of Internal Medicine, Ege University, Izmir, Turkey; 5 Unit of General Surgery 2, Department of Surgery, IRCCS Policlinico 6

Division of Surgery, CLINTEC, Karolinska Institutet at Karolinska

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San Matteo, Pavia, Italy;

University Hospital, Stockholm, Sweden;

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Division of Gastroenterology, CLINTEC, Karolinska

Institutet at Karolinska University Hospital, Stockholm, Sweden; 8 Division of Epidemiology and

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Biostatistics, European Institute of Oncology, Milan, Italy.

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This study was conducted as a project of the 6th Pancreas2000 education and research program initiated by the Karolinska Institutet and the European Pancreatic Club (EPC).

Correspondence to:

ACCEPTED MANUSCRIPT Giovanni Marchegiani, MD Unit of Surgery B, The Pancreas Institute University of Verona Hospital Trust

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P.le L.A. Scuro 10, 37134 Verona, Italy Phone +39-0458124553; Fax +39-0458124662

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Email: [email protected]

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* Marco Del Chiaro and Roberto Salvia share the senior authorship.

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Keywords: cystic lesion of the pancreas, cancer, extrapancreatic tumors, follow up

Contributions: 2

ACCEPTED MANUSCRIPT Giovanni Marchegiani: Study conception and design, interpretation of data, manuscript drafting. Giuseppe Malleo: Study conception and design, statistical analysis, interpretation of data, manuscript drafting.

Patrick Wenzel: Data collection, critical review of the manuscript.

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Jan G. D’Haese: Study conception and design, critical review of the manuscript.

Muharrem Keskin: Data collection, critical review of the manuscript.

Luigi Pugliese: Study conception and design, critical review of the manuscript.

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Alex Borin: Data collection, critical review of the manuscript.

Valentina Benning: Data collection, critical review of the manuscript.

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Linda Nilsson: Data collection, critical review of the manuscript. Nevin Oruc: Critical review of the manuscript.

Ralf Segersvard: Critical review of the manuscript. Helmut Friess: Critical review of the manuscript.

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Roland Schmid: Critical review of the manuscript.

Matthias Löhr: Study conception and design, critical review of the manuscript. Patrick Maisonneuve: Statistical analysis supervision, critical review of the manuscript.

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Claudio Bassi: Study conception and design, critical review of the manuscript. Güralp O. Ceyhan: Study conception and design, critical review of the manuscript.

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Roberto Salvia: Study conception and design, critical review of the manuscript. Marco Del Chiaro: Study conception and design, critical review of the manuscript.

Fundings: The authors did not receive any financial support for this study. Competing Interests: None declared

Abstract: 3

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Background & Aims: The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPN) is controversial. We performed a multi-center observational

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study to assess the incidence of EPN after IPMN diagnosis.

Methods: Patients with IPMNs were evaluated from 2000 through 2013 at 4 academic institutions in Europe for development of EPN. We excluded patients with an EPN previous or synchronous to the IPMN,

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and patients who had been followed for less than 12 months. Among 1340 patients with IPMNs, we calculated the incidence of EPN among patients of different sexes and ages; the standardized incidence

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ratio (SIR), and the 5- and 10-year cumulative incidence rates were calculated.

Results: Two-hundred ninety patients developed an EPN (prevalence of 21.6%) after diagnosis with IPMN. Of patients with EPN, an IPMN was discovered incidentally in 241. Among 816 patients without EPNs, 50

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developed an EPN after a median time of 46 months from study enrollment. The incidence of any EPN was not greater in patients with than without IPMN with a SIR of 1.48 (95% confidence interval, 0.94-2.22) in men and of 1.39 (95% CI 0.90-2.05) in women. The 5- and 10-year cumulative incidence rates for

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development of EPN in patients with IPMN were 7.9% and 16.6% in men, and 3.4% and 23.1% in women.

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Conclusions: Patients with IPMN do not have a significantly higher incidence of EPN than the general European population. It might not be necessary to screen patients with IPMN for EPN.

Introduction 4

ACCEPTED MANUSCRIPT Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been increasingly diagnosed during the last decades, thanks to the widespread use of cross-sectional abdominal imaging [1-3]. Different reviews of magnetic resonance imaging (MRI) examinations or computed tomography (CT)-scans in cohorts of patients without a known history of pancreatic diseases

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reported a prevalence of cystic lesions in the pancreas (of which the majority were presumably IPMNs) ranging from 1.2% to 13.5%, and increasing with age [4-6]. The high frequency of IPMNs and the potential to develop into invasive cancer led to the optimal management strategy being

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intensively debated, according to the presence of symptoms and morphologic features on crosssectional imaging [7-12].

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In addition, it has been acknowledged that patients with IPMN have a greater risk of harbouring extrapancreatic neoplasms (EPN). This notion comes from several retrospective studies showing that the prevalence of EPN previous and synchronous to the IPMN was greater than controls [1321]. The implications of these findings are relevant, because a systematic cancer screening program

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may be warranted in IPMN patients. This would lead to a substantial life-lasting impact of being at increased medical observation, as well as to an increase of the utilization of economic resources for the national health systems. However, there is little information about the development of new EPN

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during the surveillance of IPMNs. A single study from Japan suggested that the incidence of EPN after the IPMN diagnosis was not greater than in the general population, and concluded that a

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comprehensive cancer screening is not necessary [22]. We conducted a multicentre observational analysis at four European academic institutions. After assessing the EPN prevalence, the analysis was limited to patients who were free of EPN at the time of IPMN diagnosis, with the primary aim of investigating the actual incidence of EPN.

Patients and Methods

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ACCEPTED MANUSCRIPT Study design This study was approved by the local Institutional Review Boards, and data was reported according to the STROBE statement (http://www.strobe-statement.org). Patients with presumed IPMN who have been observed from January 2000 through December 2013 at the Unit of Surgery B, The

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Pancreas Institute, University of Verona Hospital Trust; the Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm; the Departments of Surgery and Gastroenterology, Klinikum rechts der Isar, Technische Universität München, Germany; and the Division of Gastroenterology,

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Ege University, Izmir, Turkey were considered for inclusion in the study. The tumor prevalence was calculated at the time of IPMN diagnosis; tumors that were synchronous to the IPMN (± 3

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months) were included in the prevalence analysis. The 3-month cut-off was chosen because this is the minimum possible follow-up interval according to the Sendai guidelines. Consequently, time to follow-up has been calculated from this time point. To estimate the actual EPN incidence, only patients who were free from them at three months from IPMN diagnosis and with a minimum

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follow-up of 12 months were analyzed. Figure 1 shows the study flowchart.

Clinical and radiologic work-up

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IPMN were defined and managed according to the evidence that was current at the time of diagnosis. In particular, the Sendai consensus guidelines were generally followed at all the

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participating institutions after their publication in 2005 [2]. The diagnostic work-up included highresolution cross-sectional imaging (computed tomography or magnetic resonance imaging). To minimize any diagnostic bias, the depiction of a communication between the cystic lesion and the main pancreatic duct was an absolute criterion to define branch-duct and mixed-type IPMNs. An endoscopic ultrasonography (EUS), with or without fine needle aspiration for cyst fluid analysis and cytology, was performed as a second line examination, according to the Sendai guidelines. Patients underwent physical examination, medical history evaluation, and routine blood tests that included tumor markers, glycaemia and amylase levels. Follow-up in patients who underwent 6

ACCEPTED MANUSCRIPT operative resection was normally carried out on a yearly basis, although – when needed – the frequency of the visits was modified at the physician’s discretion. At the follow-up visits, patients were requested to bring any kind of medical documentation not directly related to the IPMN (including results from National cancer screening protocols). This documentation was thoroughly

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reviewed during the visit, and new EPN were recorded in a prospectively maintained electronic database. If a new EPN was suspected on cross-sectional imaging performed for the IPMN surveillance, the patient underwent a further specific diagnostic work-up, including cytologic or

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histologic confirmation as appropriate.

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Statistical analysis

The expected number of EPN in patients included in the incidence analysis was calculated using sex-specific, age-standardized data and estimates on the incidence of cancer in Italy, Sweden, Germany and Turkey, obtained from national registries [23] and the GLOBOCAN project of the

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International Agency for Research on Cancer (IARC). For the specific purposes of the analysis, incidence rates in the missing years were imputed by linear extrapolation. The standardized incidence ratio (SIR) was calculated as the ratio of the observed to the expected number of patients

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developing EPN during follow-up. The 95% confidence interval (CI) of the SIR was estimated using the Wilson and Hilferty approximation of the exact Poisson distribution [24]. The SIR was

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considered significant when all values in the 95% CI were either below or above the unity. The cumulative risk function, calculated according to the method of Kaplan and Meier, was plotted to estimate the incidence of EPN in the study population. Risk factors for the development of new EPN were investigated using a Cox proportional hazard model. Factors (sex, age, symptoms, smoking history, diabetes, IPMN morphologic type) were entered into the model as a single block. The statistical package for social sciences (SPSS) 21 software (SPSS Inc, an IBM company, Chicago, IL) was used for all analyses.

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Results Patient characteristics The study population consisted of 1340 patients. Table 1 summarizes the patient characteristics. As

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already shown in previous literature [7-9], IPMNs occurred most frequently in women in their sixties, and were diagnosed incidentally in 76% of the cases. The most common presenting symptom was abdominal pain (22.1%). Diabetes mellitus was present in 10.3% of the study

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population. The vast majority of lesions were identified as branch-duct IPMNs (82.7%); the cysts were located throughout the pancreatic gland, without a predominant location. Only 14% of patients

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(189/1340) were managed surgically. In particular, 90 patients met the resection criteria at the time of IPMN diagnosis, whereas 99 patients were operated on after a follow-up period, because of the detection of morphologic changes suggestive of malignant transformation.

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Extrapancreatic neoplasms at the time of IPMN diagnosis

At the time of IPMN diagnosis, 290 patients had either a personal history of a past or a concurrent, pathologically confirmed EPN. In particular, 250 individuals had one EPN, 37 had two, and 3 had

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three tumors, resulting in a person prevalence of 21.6% (290/1340), and in a tumor prevalence of 24.8% (333/1340). Two hundred seventy-seven tumors (83.1%) occurred before the IPMN

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diagnosis, 56 (16.9%) were synchronous with the IPMN. One hundred forty-eight tumors were observed in male, the most common being kidney carcinoma (41 cases), colorectal carcinoma (36 cases), prostate carcinoma (30 cases), melanoma (9 cases), and hematologic neoplasms (7 cases). One hundred eighty-five tumors were observed in women, the most common were breast carcinoma (71 cases), colorectal carcinoma (28 cases), gynecologic neoplasms (21 cases), hematologic neoplasms (11 cases), lung adenocarcinoma (10 cases), and kidney carcinoma (10 cases). Stratification according to the IPMN diagnosis (incidental versus symptoms) showed an excess of prevalent cancer in the incidental diagnosis group (p=0.003, OR 1.68, 95% CI 1.20-2.36). In

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ACCEPTED MANUSCRIPT particular, among the 290 patients with a past or concurrent EPM, 241 had an asymptomatic IPMN and 49 a symptomatic IPMN. There was no difference when stratifying by IPMN morphologic type (main-duct versus mixed-type versus branch-duct) and by patient geographic origin (data not

Development of extrapancreatic neoplasms during follow-up

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shown).

In the cohort analysed for EPN incidence (816 patients, median follow-up of 46 months, range 13-

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170), 50 new neoplasms were detected between 4 and 136 months (22 on average) after the initial diagnosis of IPMN. Twenty-four EPM developed in males, and 26 in female patients. Two cases of

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non-melanoma skin cancers were excluded from the SIR calculation because this neoplasm type is not included in tumor registries. The SIR of any EPN was 1.48 (95% CI 0.94-2.22) in males and 1.39 (95% CI 0.90-2.05) in females. Table 3 shows the observed number and the SIR of each EPN stratified by tumor site. We observed a significantly increased incidence of kidney and gastric

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cancers in males (SIR = 9.10, 95% CI 2.45-23.30; and SIR = 5.19, 95% CI 1.04-15.17 respectively), and of melanoma in females (SIR = 9.32, 95% CI 3.01-21.76). The incidence rate, calculated using the Kaplan-Meier risk function, was not different when stratifying by sex (log-rank p=0.176, Figure

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2). In particular, the 5- and 10-year cumulative incidence of all EPN was 7.9%, and 16.6% in males, and 3.4%, and 23.1% in women. Similarly, we did not observe any difference in EPN incidence

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when stratifying patients by IPMN morphologic type and by patient geographic provenance (data not shown). The Cox proportional hazard model showed that only age was a significant risk factor for the development of new EPNs (p=0.019, HR=1.15, 95% CI 1.12-1.21).

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Discussion This multicentre study included a large cohort of patients from four European academic medical centres, with the aim to assess the association between IPMN of the pancreas and EPNs. The notion that IPMN patients are at risk of harboring EPN has been much debated in recent years, and it is

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based on a number of retrospective, case-control studies that estimated the prevalence of malignancies previous or synchronous to the IPMN. Furthermore, the majority of these reports suffer from recruitment bias, because they included only patients who underwent operative

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resection, and who were older and most likely to have a past history of other neoplasms [13-18]. A multicentre report from Italy that included both patients enrolled in a radiologic surveillance

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protocol (more than 80% of the study cohort) and patients undergoing resection, demonstrated an EPN prevalence of 23.6% [21]. In this series, the most common malignancies were breast, colorectal, kidney, prostate, thyroid carcinomas, and hematologic neoplasms. Interestingly, the prevalence of EPN was greater in patients with a first-degree family history of gastric of colorectal

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cancer. Although the authors claimed the potential for systematic cancer surveillance in IPMN patients, there was no information about the incidence of new malignancies after the IPMN diagnosis, thus limiting the strength of the study conclusions. In general, only a few reports

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attempted to estimate the incidence of EPN, but the study population or the follow-up length were

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inadequate to draw meaningful conclusions [19,20]. The only study that evaluated prospectively the incidence of EPN in patients with IPMN was published by the group from Tokyo University [22]. This research compared the occurrence of EPN in patients who were free of them at the time of IPMN diagnosis with age-stratified and sex-specific data on the incidence of cancer, obtained from the national cancer observatory. Most of the patients included in the analysis had a BD-IPMN; only 7% ultimately underwent a pancreatic resection. In this cohort, the EPN prevalence was 26.0%, and – among the 475 patients analyzed for incidence – 39 developed an EPN (median follow-up of 50 months). The incidence of all EPN was 1.3% per year, with a SIR of 0.94 (95% CI 0.67-1.29). The 5- and 10-year rates of developing any EPN were 5.7% and 12.5%. Subgroup analyses showed no 10

ACCEPTED MANUSCRIPT significant differences in sex, body mass index, diabetes, smoking history and size of IPMNs between patients developing EPN and the other patients, except in age, by Cox proportional hazard model analysis. These results indicated that an intensive screening for extrapancreatic cancers is not necessary in patients with IPMN during follow-up.

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The present study included patients from four different countries covering the Mediterranean, central and northern Europe, with the primary aim of estimating the EPN incidence during the follow-up of IPMNs. For this purpose, we divided the observation period into two discrete

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intervals: a prevalence period, in which patients already diagnosed with an EPN were identified and excluded from the incident condition risk set; and an incidence period, in which new EPN were

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observed and registered in a prospectively maintained database. The date of IPMN diagnosis was used to define the end of the prevalence period and the beginning of the incidence period. This approach was analogous to the report by Kawakubo et al [22]. The initial study population, composed of 1340 patients, is by far the largest IPMN dataset ever analyzed. Similarly to the other

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reports in the literature [21], the EPN prevalence at the time of IPMN diagnosis was in excess of 20%, and the vast majority of prevalent cancers were seen in patients with an asymptomatic IPMN. The most frequent tumors in our cohort were kidney, colorectal and prostate carcinoma in men, and

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breast, colorectal and gynecologic malignancy in females. The pattern of EPN at the diagnosis of IPMN correlated with the most prevalent malignancies in Europe (prostate, colorectal, breast,

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kidney, and gynecologic malignancies), except for frequency. The exclusion of patients with a prevalent EPN and of patients with a follow-up period < 12 months, limited the incidence analysis to a sample of 816 patients. The new EPNs were analyzed regardless of the initial management of IPMN (surveillance or operative resection). At a median follow-up of 46 months, 6.1% of patients developed an EPN (50 new cases). The incidence of EPN was not significantly greater than expected, the SIR being 1.48 (95% CI 0.94-12.22) in males and 1.39 (95% CI 0.90-2.05) in females. After stratification by tumor site, we observed a significantly increased incidence of kidney and gastric cancers in males (SIR = 9.10, 95% CI 2.45-23.30; and 11

ACCEPTED MANUSCRIPT SIR = 5.19, 95% CI 1.04-15.17 respectively), and of melanoma in females (SIR = 9.32, 95% CI 3.01-21.76). The reason for these observations remains controversial. Regarding skin melanoma, families with both melanoma and pancreatic cancer are extremely rare, and some are affected with the autosomal dominant inherited familial atypical multiple mole melanoma-pancreatic cancer

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(FAMMM-PC) syndrome [25,26]. In our analysis of BD-IPMN, patients with melanoma had not a familial history of pancreatic cancer. Thus, a diagnostic bias may have occurred, because IPMN patients are at increased medical observation and may benefit of early cancer diagnosis. As

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expected, the risk of developing an EPN grew over time, with a 5- and a 10-year cumulative incidence of 7.9%, and 16.6% in males; and of 3.4%, and 23.1% in women. The incidence of EPN

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was independent from the IPMN morphologic type, suggesting that different IPMN types are not associated with peculiar extrapancreatic cancer pathways. However, our study population was mainly composed of BD-IPMNs that were managed conservatively, such that a pathologic diagnosis including the histologic background could not be made. Similarly to the paper by

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Kawakubo et al, age resulted in being the only significant risk factor for the development of new EPN during IPMN follow-up, with a hazard ratio of 1.15 (95% CI 1.12-1.21). How should these data be interpreted? Although many authors concluded that EPN occur with

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unusual frequency in IPMNs, or that patients with IPMN are at “increased risk” of harboring an EPN, we’d rather believe that cancer patients, being enrolled in strict follow-up protocols, are more

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frequently diagnosed with small and asymptomatic IPMNs. In fact, we observed a large excess of prevalent EPNs in patients with incidentally found IPMNs. Nowadays, the follow-up protocol of the most common extra-abdominal cancers (breast carcinoma, lung carcinoma, and hematologic malignancies) includes abdominal imaging, and IPMNs are being better detected by radiologists, even in community hospitals. Taken together, these findings would justify the high prevalence of EPNs at the time of IPMN diagnosis. The incidence of new EPNs during the follow-up was not significantly greater than expected, similarly to what observed in Japan by Kawakubo et al. A word of caution: whereas in the Japanese 12

ACCEPTED MANUSCRIPT paper the SIR of all EPN was 0.94 (95% CI 0.67-1.29), in our study the SIR was 1.48 in males and 1.39 in females, with the lower bound of the 95% CI being close to the unity. This might indicate that a trend towards observing new EPN earlier than in the general population might exist, presumably because of a lead-time bias. In other words, patients who are enrolled in an IPMN

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surveillance program are followed more closely, and therefore more likely to have EPN detected during follow-up.

As specified in the methods section, we have considered a 3-month cut-off to define EPN as

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incident, because this is the minimum possible follow-up interval according to the Sendai guidelines. These guidelines have been updated in 2012, and a less stringent time interval for

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follow-up of 6 months has been proposed for IPMN lacking of “worrisome features” [27]. Had we considered this interval for the end of the prevalence period, we would have classified eight neoplasms as prevalent, (four colorectal, two breast, one prostate, and one melanoma respectively). Thus, the resulting SIR would have been 1.35 (95 % CI 0.84-2.07) in males and 1.05 (95 % CI

controls.

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0.63-1.65) in females. This would reinforce the concept that EPN incidence is not greater than

This study has some inherent limitations. First, the control population did inevitably comprise

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patients with IPMNs, that – when malignant – are not tracked in cancer registries, but rather included as pancreatic cancers. Second, cancer registries may not cover the whole national territory.

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The methods of prevalence estimation are country specific, and the quality of the estimation depends upon the amount of the information available for each country. According to the scoring system established by the IARC at the national level, all the registries included in the control group were of high quality. In particular, the Swedish national registry has coverage greater than 50% (class A), and the Italian and the German registries cover between 10% and 50% of the country population (class B). The Turkish registry covers less than 10% of the country population, but includes the Izmir local registry, where the Turkish patients enrolled in the present analysis come from. Nevertheless, cancer registries are the most reliable tools to assess population-based statistics 13

ACCEPTED MANUSCRIPT on cancer, and data are obtained easily and without any cost. Other authors used as control groups cohorts of patients with pancreatic cystic lesions different from IPMNs, or patients who underwent cross-sectional abdominal imaging for a non-pancreatic indication [13]; but this would have implied a systematic analysis of radiologic reports, and possibly a central review of images. Furthermore,

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many abdominal imaging protocols for common non-pancreatic indications (i.e. kidney stones) do not include intravenous dye, and thus would not be accurate to detect small pancreatic cysts. In conclusion, this large, multicentric European observational study showed that the incidence of

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new EPN during the follow-up of pancreatic IPMNs is not significantly greater than in the general population. Accordingly, a comprehensive EPN screening outside the national protocols might not

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be strictly necessary.

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Figure legends: 1. Study flowchart

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2. Risk function curves for the development of EPN, stratified by sex. Log rank test, p=0.176

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26. Poley JW, Kluijt I, Gouma DJ, et al. The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. Am J Gastroenterol

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97

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for the management of IPMN and MCN of the pancreas. Pancreatology 2012; May-Jun;12(3):183-

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ACCEPTED MANUSCRIPT

RI PT

Tables

N (%) 545 (40.7) 795 (59.3)

M AN U

67 (16-94) 316 (23.6) 1024 (76.4) 1138 (84.9) 202 (15.1) 1302 (97.2) 38 (2.8)

AC C

EP

TE D

Variable (N=1340) Sex M F Median age at the time of IPMN diagnosis (years) IPMN diagnosis Symptoms Fortuitous General symptoms No Yes Jaundice No Yes Weight loss No Yes Abdominal pain No Yes Diabetes No Yes Acute pancreatitis No Yes Chronic pancreatitis No Yes Morphologic type MD-IPMN Mixed-type IPMN BD-IPMN

SC

Table 1. Demographic and clinical characteristics of the study population

1234 (92.1) 106 (7.9) 1044 (77.9) 296 (22.1) 1202 (89.7) 138 (10.3) 1238 (92.4) 102 (7.6) 1276 (95.2) 64 (4.8) 73 (5.4) 159 (11.9) 1108 (82.7)

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ACCEPTED MANUSCRIPT Tumor localization Head Uncinate process Body Tail Multifocal Median cyst size (mm) Mean serum Ca 19.9*

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies.

The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPNs) is controversial. We performe...
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